The Risk of Recurrence in Breast Cancer Patients Treated with Tamoxifen: Polymorphisms of CYP2D6 and ABCB1

CYP2D6 plays a major role in the metabolism of tamoxifen, and polymorphism of Pglycoprotein has been associated with resistance of many drug therapies. This study investigates the clinical impact of genetic variants of CYP2D6 and ABCB1 in breast cancer patients treated with tamoxifen. Blood samples from 95 breast cancer patients treated with tamoxifen were collected and genotyped for CYP2D6 and ABCB1 variants using allele-specific PCR method. Recurrence risks were calculated using Kaplan–Meier analysis and compared using the log-rank test. Patients carrying CYP2D6*10/*10 and heterozygous null allele (IM) showed higher risks of developing recurrence and metastasis (OR 13.14; 95% CI 1.57–109.94; P=0.004) than patients with CYP2D6*1/*1 and *1/*10 genotypes. Patients with homozygous CC genotypes of ABCB1 C3435T showed a shorter time to recurrence. Patients who were CYP2D6 IM and homozygous CC genotype of C3435T have statistically significant higher risks of recurrence (P=0.002). Similarly, median time to recurrence in these patients was only 12 months (95% CI=0.79–23.2) compared to those without this combination which was 48 months (95% CI=14.7–81.2). Patients with CYP2D6 IM and homozygous CC genotype of ABCB1 C3435T have shorter times to recurrence. The results confirmed the findings of previous studies and support FDA recommendation to perform pre-genotyping in patients before the choice of therapy is determined in breast cancer patients

Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians

<p>Abstract</p> <p>Background</p> <p><it>CYP2C9 </it>and <it>VKORC1 </it>are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs) in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients.</p> <p>Methods</p> <p>Direct sequencing method was used to identify SNPs in <it>CYP2C9, VKORC1, CYP4F2, EPHX1, PROC </it>and <it>GGCX </it>genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing.</p> <p>Results</p> <p>From the 40 SNPs analyzed, <it>CYP2C9 </it>rs17847036 and <it>VKORC1 </it>rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between <it>CYP2C9*3, CYP2C9C</it>-65 (rs9332127), <it>CYP4F2 </it>rs2108622, <it>GGCX </it>rs12714145, <it>EPHX1 </it>rs4653436 and <it>PROC </it>rs1799809 with warfarin sensitivity.</p> <p>Conclusions</p> <p><it>VKORC1 </it>rs9923231 AA and <it>CYP2C9 </it>rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively). <it>CYP2C9 </it>and <it>VKORC1 </it>genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.</p

Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin

What is known and Objectives:  Testing for cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia. Methods:  Patients who were attending clinics at our hospital and prescribed warfarin with stabilized INR levels of 2-4 were selected. DNA was extracted from blood samples and subsequently genotyped for CYP2C9*1, *2, *3, VKORC1 (G-1639A) and VKORC1 C1173T. Linear regression modelling using age, CYP2C9 and VKORC1 genotypes, sex, weight and height was undertaken to define a warfarin dosing algorithm. An initial model was developed using data from one cohort of patients and validated using data from a second cohort. Results and Discussion:  A model which included age and variants of CYP2C9 and VKORC1 account for about 37% of the variability in warfarin dose required to achieve INR of 2-4. Among the parameters evaluated, only VKORC1 (G-1639A) and (C1173T) alleles, and age correlated with warfarin dose at 6 month. The mean dose predicted using the algorithm derived from cohort 1 was lower than the actual dose for cohort 2 (3·30 mg, SD 0·84 vs. 3·45 mg, SD 1·42). There was no relationship between INR values and the dose taken by the patients. Race, sex, weight and height did not correlate with dose. What is new and Conclusion:  This study identifies factors which affect warfarin dosing in the Malaysia population. However, our best model does not account sufficiently for the variability in dose requirements for it to be used in dose prediction for the individual patient. Other important influential factors affecting warfarin dose requirement remain to be identified

Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects

Cognitive impairment is associated with increased blood concentrations of homocysteine and high blood viscosity. Previous studies have shown that vitamin B supplementation reduces homocysteine and enhances cognitive function in patients with mild dementia and low serum folic acid. However, whether folic acid enhances cognitive function in elderly subjects without dementia and normal serum folic acid is unknown. Twenty-four healthy elderly subjects (age 73.0+/-5.6 years, mean+/-S.D.) with normal serum folic acid (6.3+/-2.4 microg/l) and Mini Mental State Examination (MMSE) >27/30 were randomized to 4-week treatment with folic acid 5mg/day or placebo in a randomized, placebo-controlled, parallel-group study. Continuous Attention Test (CAT), Four-Choice Reaction Time (FCRT), Digit-Symbol Substitution (DSS), Scanning Memory Sets (SMS), and blood viscosity for different shear rates were measured before and after treatment. Folic acid supplementation induced a significant increase in serum folic acid levels (+13.8 versus +1.6 microg/l, p<0.001) and fall in homocysteine levels (-1.91 versus -0.41 micromol/l, p=0.05) compared to placebo. However, there was no significant change in CAT, FCRT, DSS, SMS, and blood viscosity between the two groups. Short-term folic acid supplementation does not enhance psychomotor performance or reduce blood viscosity in healthy elderly subjects with normal serum folic acid levels and preserved cognitive function

High occurrence of CYP3A5 variants among breast cancer and organ transplant patients

Abstract CYP3A5 is one of the important drug metabolising enzyme and its polymorphism shows marked differences in protein expression and catalytic activities between different geographical ethnic groups. Both tamoxifen and tacrolimus are substrates of CYP3A5 and thus the polymorphism may cause pharmacokinetics variation which explains the wide variaton in the dose requirement and patients’s responses. CYP3A5*3 (A22893G) allele resulted in a truncated protein with loss of CYP3A5 expression whilst the CYP3A5*6 (G 30597A) allele caused deletion of exon 6 from the splice variant and was associated with lower CYP3A5 catalytic activity. Both of these polymorphisms lead to the inability of an individual to express full functional CYP3A5. Aim This study aims to investigate the frequency of CYP3A5 haplotypes among healthy volunteers, breast cancer and kidney transplant patients in selected hospitals. Methods This study was approved by the Medical Research Ethic Committee and local institution. Subjects were screened for inclusion and exclusion criteria and recruited after informed consent. Five ml of blood was obtained from subjected and DNA was extracted and subjected to genotyping of CYP3A5 variants. Multiplex PCR were designed with novel primers specific to 3’ end that amplify the variants of A6986G and G14690A. The optimized method was validated by direct sequencing. Result Twelve breast cancer patients (tamoxifen therapy), 6 organ transplant patients (tacrolimus therapy) and 264 healthy blood donors (98 Malay and Chinese; 74 Indian) were successfully recruited. CYP3A5 is highly polymorphic in the Malaysian populations with the *3 allele having a frequency of more than 60% among the healthy volunteers. The frequency of *3 allele was lower (54.17%) in breast cancer patients. All the 6 patients treated with tacrolimus carry at least one mutated variant (1 patient was heterozygous and 5 were homozygous CYP3A5*3). CYP3A5 *6 allele was absent all patients. Conclusion High percentage of patients and volunteers carry at least one CYP3A5*3 allele and this may be an important genetic contributor to interindividual as well as interethnic differences in the clearance of CYP3A5 substrates. However, we are conducting an on-going study with a larger sample size of the patients to understand the impact of pharmacodiagnostics of drug metabolizing enzyme and drug receptors in local clinical settings

A horizon scan for temperate pastoral weed science–a New Zealand perspective

Pastures represent about half of the global agricultural area and productivity losses from weeds are significant. The complex interactions between them and other pasture plants, livestock and the environment imply a need for innovative research that transforms pasture management. To this end, a horizon scan was conducted to identify relevant issues, questions, opportunities, and drivers. The drivers were ranked using three criteria: (1) is this a horizon (is the driver likely to become important in 10–20 years?); (2) will the research require stretchy science (is it currently not well addressed by the science community?); (3) is the research transformative (will successful scientific research in this area lead to significant changes to weed management in pastures?). We identified 11 major issues and 46 subordinate ones. The three highest ranked major issues were: (1) anticipated reductions in access to herbicides; (2) rethinking weed management under an ecosystem services paradigm; (3) responding to shifts in best practice and the regulations that are altering farm system planning to reduce farming’s environmental impacts. We conclude that fundamental interdisciplinary research is needed that addresses biosecurity and weed management issues, while reducing the environmental footprint of farming and maintaining productivity

The Risk of Recurrence in Breast Cancer Patients Treated with Tamoxifen: Polymorphisms of CYP2D6 and ABCB1

CYP2D6 plays a major role in the metabolism of tamoxifen, and polymorphism of P-glycoprotein has been associated with resistance of many drug therapies. This study investigates the clinical impact of genetic variants of CYP2D6 and ABCB1 in breast cancer patients treated with tamoxifen. Blood samples from 95 breast cancer patients treated with tamoxifen were collected and genotyped for CYP2D6 and ABCB1 variants using allele-specific PCR method. Recurrence risks were calculated using Kaplan–Meier analysis and compared using the log-rank test. Patients carrying CYP2D6*10/*10 and heterozygous null allele (IM) showed higher risks of developing recurrence and metastasis (OR 13.14; 95% CI 1.57–109.94; P = 0.004) than patients with CYP2D6*1/*1 and *1/*10 genotypes. Patients with homozygous CC genotypes of ABCB1 C3435T showed a shorter time to recurrence. Patients who were CYP2D6 IM and homozygous CC genotype of C3435T have statistically significant higher risks of recurrence (P = 0.002). Similarly, median time to recurrence in these patients was only 12 months (95% CI = 0.79–23.2) compared to those without this combination which was 48 months (95% CI = 14.7–81.2). Patients with CYP2D6 IM and homozygous CC genotype of ABCB1 C3435T have shorter times to recurrence. The results confirmed the findings of previous studies and support FDA recommendation to perform pre-genotyping in patients before the choice of therapy is determined in breast cancer patients